OCULAR & VISUAL
SIDE EFFECTS
of
SYSTEMIC DRUGS
Clinically Relevant Toxicology and Patient
Management
n Valerie Q. Wren, O.D.
Abstract
Many systemic drugs have reported ocu-
lar and visual side effects that impact pa-
tient management. It is important to be
familiar with the associated side effects
which can be mild and transient or may
seriously threaten vision. This article
deals briefly with the mechanisms and
reasons that account for the effects that
systemic drugs can exert on the visual sys-
tem. The remainder of the paper will
cover major drug classes and serve as a
guide to familiarize clinicians with impor-
tant ocular and visual implications.
Key Words
Melanin binding, photosensitizer, sys-
temic drugs, ocular toxicity, ocular and
visual side effects
n Journal of Behavioral Optometry
M any common systemic medi-
cations can affect ocular tis-
sues and visual function. Adverse effects
can have mild to more serious implica-
tions. The optometrist is in the ideal posi-
tion to identify and manage such
occurrences. In order to appropriately ed-
ucate patients, prevent and minimize seri-
ous consequences, clinicians should keep
in mind the potential effects from sys-
temic drugs. While this is true for all op-
tometrists, it is particularly important for
those with special interest and expertise in
the diagnosis and treatment of functional
and behavioral visual problems. These
practitioners are most apt to treat patients
with special visual needs, such as those
with learning disabilities and acquired
brain injuries. These patients are quite
frequently taking some type of medica-
tion(s).
Every year there are many new drugs
approved by the FDA (Food and Drug Ad-
ministration). It can be a formidable task
to keep track of newly released drugs as
well as those already on the market. There
are some drugs that are well documented
in terms of their ability to affect the eye.
For example, it is well known that
chloroquine and hydroxychloroquine can
cause permanent, sight-threatening
retinopathy.1 However, side effects from
newer drugs and commonly used drugs
may not be universally known.
One of the most important aspects of
the patient intake is obtaining a thorough
medical history which includes specific
medications, dosage, and duration of
treatment. Some drugs have a greater pro-
pensity to cause toxicity the longer the
drug is used. Others tend to affect the eyes
more if used in higher dosages. In general,
it is a good idea to identify the condition
being treated since many drugs have mul-
tiple approved and off-label uses. For in-
stance, beta-blockers are used to treat
hypertension, arrhythmia, angina, and mi-
graines.
The eye care practitioner can be instru-
mental in detecting and reporting ocular
side effects, advising patients, plus collab-
orating with other members of the pa-
tients healthcare team. One of the
difficulties includes becoming familiar
with the countless systemic medications
prescribed for patients. Another is being
able to correlate a particular side effect
with a suspected drug. It is the vision care
practitioners responsibility for eye care
practitioners to maintain current pharma-
cologic knowledge. This article will deal
briefly with how and why systemic drugs
can affect the eyes. The remainder of the
paper will cover major drug classes and
serve as a guide to familiarize clinicians
with important ocular implications. Ap-
pendix A further delineates the commonly
prescribed drugs in each class, while Ap-
Volume 11/2000/Number 6/Page 149
pendix B can serve as a clinically relevant
summary of the ocular and visual side ef-
fects of each class of drugs.
ANATOMY
The total area of the globe is relatively
small compared to the rest of the body.
When a systemic medication is taken to
treat another part of the body, the eyes fre-
quently are affected. After a drug mole-
cule enters the systemic circulation, it can
reach ocular tissues through uveal or reti-
nal circulations.2 The choroid, sclera and
ciliary body have thin, fenestrated walls
for drug molecules to pass. Small, lipid
soluble molecules pass freely into the
aqueous humor, and can further diffuse
into avascular structures such as the lens,
cornea, and trabecular meshwork.
At the ocular level, the ability of a drug
to penetrate the major barriers determines
its likelihood to affect ocular tissues and
visual function. The first barricade is the
blood-brain barrier where tight junctions
called zonular occludens of endothelial
cells in the retinal blood vessels prevent
passage of drug molecules. Another
blockade is the blood-aqueous barrier
whose fenestrations sort by molecular size
and lipid solubility. The blood-retinal bar-
rier restricts entry of larger molecular
weight drugs via Bruchs membrane and
the zonular occludens of the retinal pig-
ment epithelium (RPE).
Drug molecules that enter by means of
the uveal circulation exit the eye from the
Canal of Schlemm, ciliary body or may
diffuse into adjacent anatomical struc-
tures. Drugs from the retinal circulation
can reenter the systemic circulation, dif-
fuse into the vitreous and anatomical
structures, or get actively transported out.
In summary, drug molecules can enter
the eye, contact various ocular tissues, and
eventually accumulate in ocular tissues or
exit the eye. There are three major accu-
mulation sites including the cornea, lens
and vitreous. The duration of drug in the
eye is prolonged if deposited, increasing
chances for toxicity.2 The cornea has a
permeable endothelium, and the stromal
glycosaminoglycans (GAGs) can bind
drug molecules, leading to edema and de-
creased transparency. Drug molecules
can also bind to lens protein, and photo-
sensitize the lens to ultraviolet (UV) radi-
ation. Lastly, drug molecules tend to
accumulate in the vitreous due to the slow
rate of fluid exchange.
Volume 11/2000/Number 6/Page 150
MELANIN BINDING mia, or hyperlipidemia.4 Beta-blockers,
used to treat hypertension, reduce tear
Melanin binding and storage of drug
lysozyme levels and immunoglobulin A
molecules has been postulated as a precur-
(IgA).5 This causes a reduction in tear se-
sor to ocular toxicity.2 It is possible that
cretion, and patients complain of ocular ir-
melanin absorbs light and damage results
ritation, dry eye symptoms, and contact
from the free-radical nature of melanin in
lens intolerance. Management should in-
structures such as the uveal tract and the
clude artificial tear supplementation and
RPE. Toxicity seems to occur in both al-
refitting the patient with lower water con-
bino and non-albino eyes. Certain drugs
tent soft lenses. More importantly,
like chloroquine and chlorpromazine have
nonselective beta-blockers decrease
a high affinity to melanin and tend to af-
intraocular pressure (IOP) by blocking the
fect ocular tissues. Drugs binding to mel-
Bet a- 2 ( B2) r ecepto r s o n t h e
anin may only be part of the problem,
nonpigmented ciliary epithelium.5 This
because prolonged exposure may affect
results in reduced aqueous formation by
adjacent, non-pigmented ocular tissues by
the ciliary body. Topical B2 blockers pro-
slow release of drug from pigmented tis-
duce little additional IOP reduction with
sues. The melanin theory is still being de-
concom i t ant adm i ni st r a t i o n o f a
bated, and is not completely explained.
nonselective (B1 and B2) systemic
DRUG METABOLISM beta-blocker. Some patients may be
misdiagnosed as normal tension glau-
The bodys ability to metabolize a
coma because the IOP is artificially re-
drug directly correlates with toxicity. In
duced, appearing within normal limits.
patients with liver and kidney disease,
Patients should continue taking their med-
there is a decreased rate of excretion,
ication, and the clinician should contact
which allows drug molecules to accumu-
the prescribing physician. Management
late to toxic levels.3 Also, toxic metabo-
includes changing the dosage or the medi-
lites formed elsewhere like the liver, can
cation. Other antihypertensive drugs in-
reach the eye through systemic circulation
clude angiotensin converting enzyme
or can be produced locally in ocular tis-
(ACE) inhibitors and alpha adrenergic an-
sues.
tagonists. These rarely cause ocular side
PHOTOSENSITIZERS effects.
The adult crystalline lens normally fil- Diuretics
ters most ultra-violet ( UV) radiation, so Thiazides or diuretics are often used to
there is minimal risk of UV affecting the treat congestive heart failure. Hydrochlo-
retina, where drug molecules can poten- rothiazide (HCTZ) is a commonly used
tially bind.1 UV radiation does affect an- diuretic and sometimes causes dry eye by
terior tissues like the cornea and lens changing the tear film. Myopic shift and
when photosensitized by bound drug mol- band keratopathy have been reported but
ecules. Exposed lens proteins, UV photo- rarely occur.4
sensitized by bound drug molecules, may
Antiarrhythmics
denature, opacify and accumulate leading
There are many drugs used to treat an-
to cataract formation. UV radiation can
gina including antiarrhythmics, calcium
potentially affect the retina in aphakic and
(Ca++) channel blockers, vasodilators,
pseudophakic patients, because UV can
and nitroglycerine. A well known
penetrate without the normal absorptive
anti-arrhythmic drug causing significant
lens barrier. Well-known photosensitizers
ocular side effects is amiodarone. 6
that cause anterior subcapsular lens
Amiodarone is a photosensitizer, with a
changes include allopurinol, phenothi-
tendency towards lipid storage in the cor-
azine, amiodarone, and chloroquine.
nea and lens. Studies found the presence
CARDIOVASCULAR AGENTS of amiodarone in all ocular tissues when
systemically administered.5 This medica-
Beta-blockers
tion is used when standard digitalis ther-
When patients report they have a
apy fails, and tends to cause whorl-like
heart problem, it is important to deter-
corneal deposits in as early as six days of
mine the particular condition(s) for which
treatment, but more commonly in one to
they are being treated, e.g, hypertension,
three months of treatment. The deposits
congestive heart failure, angina, arrhyth-
appear whorl-like because epithelial cells
n Journal of Behavioral Optometry
migrate centripetally from the limbus.
This keratopathy occurs in the middle to
lower third of the cornea, and Hud-
son-Stahle lines should be ruled out.
Amiodarone can also cause anterior and
posterior subcapsular lens changes since it
is a photosensitizing agent. As a preven-
tive measure, a UV blocker (400nm)
should be prescribed. Visual acuity (VA)
is not usually affected, but can be mildly
reduced (20/25-20/30). Patient symptoms
include glare, halos, and foggy vision.
This is a dose and duration dependent
drug, where toxicity increases with higher
doses and longer therapy. Fortunately, the
side effects usually regress as amiodarone
is discontinued. There have been recent
cases of optic neuropathy with vision loss
as well as reports of pseudotumor cerebri,
however these were also reversible with
the discontinuation of amiodarone ther-
apy.6,7 A dilated fundus exam, Amsler
grid, and central visual-field screening
test should be performed, and consultation
is recommended with the patients inter-
nist or cardiologist to consider alternative
therapy.6
Another drug commonly used for car-
diac arrhythmia is digitalis (Digoxin).
11-25% of patients using this drug experi-
ence some ocular symptoms like change
in color vision, visual sensation, or flick-
ering vision.4 Early reports suggested
retrobulbar optic neuritis toxicity.5 Later,
high concentrations of the drug were
found in the retina and choroid. Thus, the
retina instead of the optic nerve is thought
to be the site of digitalis toxicity. In partic-
ular, cone dysfunction is caused by inhibi-
tion of the enzyme, Na+-K+-activated
ATPase, which plays a vital role in main-
taining normal cone receptor function.5
Color vision can be monitored with the
Farnsworth 100-hue test.4 Another side
effect is reduction of IOP in glaucomatous
and nonglaucomatous eyes. 1 Cardiac
g ly c o sides like Digoxin inhibit
ouabain-sensitive Na+-K+-ATPase in the
ciliary epithelium.1 This enzyme is re-
sponsible for the active transport of so-
dium, necessary for aqueous secretion.
Thus, its inhibition leads to reduced aque-
ous secretion and IOP. Along with the oc-
ular side effects, there are numerous
systemic side effects associated with this
drug precluding its use in glaucoma treat-
ment.
n Journal of Behavioral Optometry
Antihyperlipidemics transischemic attacks (TIAs). Patients
Patients with high cholesterol are of- must discontinue oral contraception if
ten treated with antihyperlipidemic drugs. they experience TIAs due to the increased
One of the earlier investigations of risk of stroke.4
lovastatin (Mevacor), showed a high rate Lastly, women entering menopause
of lens opacities.7 However, subsequent frequently start estrogen replacement.
studies exonerated this drug showing no Similar to oral contraception, steepening
difference between the treated and pla- of corneal curvature and contact lens in-
cebo groups.8 Niacin (B3) is another drug tolerance have been noted.1 There can be
that lowers triglycerides and low-density increased risk of retinal thrombosis and
lipoproteins (LDLs). However 20% expe- optic neuritis in large doses.10
rience dry eye and several cases of cystoid
CENTRAL NERVOUS SYSTEM
macular edema have been reported. In ad-
AGENTS
dition, symptoms of lid edema and blurred
vision may occur. Central nervous system (CNS) agents
are becoming the most commonly pre-
HYPERGLYCEMICS
scribed class of medication in the world.
Sulfonylureas, such as glipizide and In general, visual acuity may be inexplica-
glyburides are used to treat diabetes.3 For bly reduced, color vision altered, pig-
some patients, subcutaneous insulin treat- mented deposits may be found on the
ment is necessary. Side effects from these endothelium or lens capsule, and optic
drugs are rare and it may be difficult to dif- neuritis may occur.
ferentiate them from secondary signs of
Antipsychotic
diabetic state or from drug related
Phenothiazines are prescribed to man-
hypoglycemia.9 These signs and symp-
age s chi zophr eni a. T h i o r i d a z i n e
toms include extraocular muscle paresis,
(Mellaril) has almost completely replaced
diplopia, and optic neuritis.4
previous chlorpromazine (Thorazine) use.
HORMONES These drugs have anticholinergic proper-
ties causing blurred vision, decreased ac-
Synthetic hormones are commonly
commodation and mydriasis. These
prescribed for replacement therapy. In pa-
s ym pt om s ar e t r an si e n t a n d
tients with reduced thyroid function,
dose-dependent. Reduced tearing and dry
levothyroxine (Synthroid) is given for
eye m ay al s o r es ul t f r o m t h e
management of thyroxine levels.3 Some
anticholinergic effects. These drugs are
patients have noticed visual hallucina-
photosensitizers and cause endothelial
tions with the use of this drug.10 Other side
and lenticular pigment deposits. Doses
effects are eyelid hyperemia and
greater than 500 mg/day given for pro-
pseudotumor cerebri (PTC), which disap-
longed periods have a higher incidence of
pear with discontinuation of the drug.7
irreversible corneal and lenticular depos-
The patients internist or endocrinologist
its.8 Pigment deposits can occur on areas
should be notified to adjust the dosage,
of the bulbar conjunctiva that are exposed
balancing adequate T-level control and re-
to UV radiation. UV protection was found
ducing side effects.4
unsuccessful to reduce the prevalence,
The use of oral contraceptives is com-
and these patients should simply be moni-
monly known to cause dry eye and contact
tored on a yearly basis. More importantly,
lens intolerance from reduced tear secre-
retinal and macular damage have been re-
tion. The exact cause has not been proven,
ported in higher doses.6 This can lead to
but may be associated with steepening of
permanent visual acuity and visual field
the corneal curvature, corneal edema from
loss if not closely monitored. However,
hypoxia, and decreased aqueous compo-
some of these changes may be reversible if
nent of the precorneal tear film.1 Also,
detected early.
there have been microvascular complica-
Lithium is a medication used to treat
tions like artery and venous occlusions re-
bipolar affective disorders, e.g., manic de-
ported in the past. These may be related to
pression. Drugs in this class (manic de-
changes in retinal vasculature, enhanced
pressives) can cause downbeat jerk
platelet adhesiveness, or increase in
nystagmus which may not reverse when
fibrinogen and clotting factors.1 Other
the drug is stopped.2 Blurred vision some-
side eff ect s i ncl ude m i gr ai nes ,
times occurs due to cortical involvement.
pseudotumor cerebri, macular edema, and
Volume 11/2000/Number 6/Page 151
Other ocular complications include
diplopia, keratitis sicca and contact lens
intolerance.
Antianxiety
There are numerous drugs used to treat
extreme tension. Ocular side effects like
blurred vision and diplopia are usually
rare and reversible.10 Mydriasis can result
with diazepam (Valium) use. Allergic
conjunctivitis may onset after 30 minutes
due to antigenic factors in this drug class.
Antidepressant
The tricyclic antidepressants are
dirty drugs in that they produce many
anticholinergic side effects. Symptoms of
blurred vision, cycloplegia and dry eye are
transient and reversible. 11 Clinicians
should use caution with sympatho-
mimetics along with tricyclics and also
with monoamine oxidase (MAO) inhibi-
tors. It is important to correlate the pa-
tients medication with the time frame of
symptoms when possible. Reducing or
changing the medication may improve the
symptoms. In some cases, near vision
lenses may be helpful.
The newer antidepressants, with fewer
systemic side effects are the selective se-
ro to nin re-uptake inhibitors like
fluoxetine (Prozac), sertraline (Zoloft),
paroxetine (Paxil) and citalopram
(Celexa).11 These do not have any signifi-
cant ocular effects.9
Barbiturate
Barbiturates are used to sedate or in-
duce sleep. Many OTC drugs are mar-
keted heavily and can be easily purchased.
Ptosis is common in habitual users.8
Extraocular muscle problems and nystag-
mus can also occur.
Anticonvulsant
These drugs are prescribed not only
for chronic epilepsy but for pain as well.
Phenytoin (Dilantin) and carbamazepine
(Tegretol) are very commonly prescribed.
These drugs can cause nystagmus, glare
and conjunctivitis.12
CNS Stimulant
Methylphenidate (Ritalin) is a mild
cortical stimulant with CNS actions simi-
lar to amphetamines or adrenergic
agonists. In adults, this drug stimulates
the sympathetic system and is helpful in
cases of narcolepsy. However, this drug
has a paradoxical effect on children, and is
frequently used to calm children with At-
Volume 11/2000/Number 6/Page 152
tention Deficit Hyperactivity Disorder
(ADHD). The visual side effects include
accommodative dysfunctions and blurred
vision.13
ANTIMIGRAINE AGENTS
Beta-blockers, discussed previously,
are sometimes used to treat migraines.
The recently popular sumatriptan
(Imitrex) is a serotonin receptor antago-
nist. Not many side effects have been re-
ported, however corneal opacities were
found in dogs. As with newer drugs, re-
porting of side effects may not be current
or accessible. Thus, it is best to take a
careful history and monitor any changes.
ANTIULCER AGENTS
Blocking histamine-2 (H2) receptors
in the stomach reduces acid production,
helpful for thousands of patients with
gastroesophageal reflux disease (GERD),
peptic ulcer and gastritis.3,10 Cimetidine
and ranitidine, better known as Tagamet
and Zantac, are common over-the-counter
(OTC) H2 blockers. Some patients have
complained of visual hallucinations,
blurred vision, photophobia, conjunctivi-
tis and color change.4 However, these side
effects are usually rare and reversible.
ANTICOAGULANTS
Blood thinners are used to treat venous
thrombosis and to prevent embolic in-
duced stroke.5 The coumadin-derived
medications, like warfarin and heparin,
potentiate retinal hemorrhaging due to
their blood thinning effect.4 This is a par-
ticular concern in patients with diabetic
retinopathy or age-related macular degen-
eration. It is important to closely follow
diabetic patients for proliferative retinal
changes. The managing physician should
be advised on the potential for retinal
hemorrhages. Also, spontaneous anterior
chamber hyphema can occur in any pa-
tient on anticoagulant treatment. Rou-
tinely, blood thinners are discontinued
before ocular surgery in diabetic and hy-
pertensive patients. This may not be nec-
essary in a healthy patient.
ANALGESICS
Salicylate, or aspirin, has multiple
therapeutic uses. Not only is it effective
for pain and fever reduction, but aspirin
also works well as a platelet inhibitor.
This anticoagulant property is helpful in
acute myocardial infarction and embolic
stroke patients. In addition, it is pre-
scribed for gout and rheumatoid arthritis.
Aside from irritation of the gastric lining,
aspirin has few systemic and ocular side
effects. In terms of management, aspirin
should not be used in patients with trau-
matic hyphema due to the increased risk
of rebleed. In contrast to blood thinners, it
does not increase risk of vitreal or
panretinal hemes in diabetics.4 It should
be noted that chronic use may cause yel-
lowing of vision.
ANTIINFLAMMATORIES
Corticosteroids
Corticosteroids are used to treat in-
flammatory and allergic conditions. They
are very effective for acute disease states
as well as chronic conditions such as
asthma and chronic obstructive pulmo-
nary disease (COPD). Cataracts resulting
from steroid use are well known and occur
with topical, systemic, and nasal adminis-
tration.14 The etiology is unknown, but
these drugs may react with amino groups
of crystalline lens fibers causing protein
complexes to aggregate. 1 Posterior
subcapsular lens opacity is the most fre-
quent and critical side effect, especially in
children since it is irreversible and ambly-
opia may result. Careful evaluation of
each patient, regardless of duration or dos-
age is important. If significant changes
are noted, the prescribing physician
should be informed to weigh the risk ver-
sus benefit of steroid treatment. Another
significant side effect from steroid use is
increased IOP. The incidence is greater
with topical versus systemic administra-
tion.1 There is increased aqueous humor
formation and reduction in aqueous out-
flow. The latter occurs with long term
t r eat m ent . E xces s i ve a m o u n t s o f
mucopolysaccharides accumulate in the
trabecular meshwork, obstructing aque-
ous outflow by hydrating the trabeculum.
This results in resistance to aqueous out-
flow and should be managed with IOP
lowering drugs, as well as changing or ta-
pering the steroid medication. Other side
effects include iris microcysts, exacerba-
tion of herpetic keratitis, papilledema, and
retinopathy.1
NSAIDs
There are much fewer side effects as-
sociated with nonsteroidal anti-inflamma-
tory drugs (NSAIDs) compared to
corticosteroids. Ibuprofen, a common
n Journal of Behavioral Optometry
OTC medication, can cause blurred vi-
sion, refractive changes, diplopia, color
vision changes and dry eye. With chronic
use, permanent vision and visual field loss
have been reported.4 The patients inter-
nist should be notified, and a neurological
workup may be indicated if there are vi-
sual field changes. Indomethacin
(Indocin) is a prescription medication that
causes whorl-like stromal opacities in
11-16% of patients. Patients may com-
plain of light sensitivity, and RPE or reti-
nal changes can occur. These usually
improve with discontinuation of the drug.
In addition, pseudotumor cerebri can oc-
cur with any NSAID, and a dilated exam
should be performed.
ANTIRHEUMATICS
One of the treatments for rheumatoid
arthritis and lupus involves gold salts
(Ridaura).15 Gold deposits can reach the
cornea and lens by circulation through the
aqueous in the anterior chamber. This can
lead to numerous, minute colored deposits
on the eyelids, conjunctiva and corneal
stroma.1 The color of these deposits can
vary from yellow-brown to violet or red.
These deposits are benign, so there is no
need to discontinue or reduce the dosage.
If the patient stops taking this medication,
the deposits usually disappear in three to
six months.
Recently, physicians have frequently
been prescribing the new Cox-2 inhibi-
tors, Celebrex and Vioxx, to treat rheuma-
toid arthritis and osteoarthritis. These
drugs seem effective in reducing inflam-
mation with less risk of peptic ulcer in
chronic users as compared to NSAIDs.
Ocular side effects are rare. Only blurred
vision has been mentioned.
ANTIALLERGY AGENTS
Blocking histamine-1 (H1) receptors
alleviates allergic conditions of rhinitis,
dermopathies, urticaria, and systemic al-
lergies. Benadryl and Chlor-trimeton are
common OTC medications, the latter
causing less sedation. The drugs in this
class reduce mucous and tear secretion
which aggravates keratitis sicca and
causes contact lens intolerance.11 Antihis-
tamines have weak atropine action, acting
as cholinergic antagonists. This can cause
mydriasis, anisocoria, decreased accom-
modation and blurred vision.
n Journal of Behavioral Optometry
ANTICHOLINERGICS
Anticholinergics and antihistamines
are present in many OTC medications
such as sedatives, sleep aids, cold prepara-
tions, antidiarrheals and nasal deconges-
tants. 16 They often inhibit glandular
secretions in a dose-dependent manner.
Ocular effects include dry eye, mydriasis
and decreased pupil response to bright
light.
Atropine and related drugs are in-
cluded in this category. Scopolamine
patches contain an antiemetic used to pre-
vent motion sickness, and are frequently
dispensed on cruise lines. Passengers may
directly contaminate their eyes after ap-
plying the transdermal patch. This leads
to anisocoria or mydriasis. Practitioners
can easily rule out any neurological asso-
ciation like a third nerve palsy because
there is no extraocular palsy and the di-
lated pupil will not constrict to 1%
Pilocarpine.
DERMATOLOGIC AGENTS
Dermatologists prescribe isoretinoin
(Accutane) to treat acne. This systemic
medication is a Vitamin A analog and fre-
quently causes blepharoconjunctivitis.9
Decreased meibomian gland function and
contact lens intolerance result from its
use. Since meibomian glands are modi-
fied sebaceous glands, suppression of
these glands by Accutane causes defi-
ciency of the normal lipid layer in the tear
film. Along with artificial tears, treatment
includes decreasing the dosage or discon-
tinuing the medication. Other reversible
side effects include keratitis, corneal
neovascularization, pseudotumor cerebri,
optic neuritis, night blindness and
retinotoxicity.1
ANTIINFECTIVES
Sulfonamides
Sulfacetamides are effective against
gram-positive and gram-negative organ-
isms. Conjunctivitis and optic neuritis are
rare, but myopic shifts commonly occur.
Symptoms resolve within days to weeks
of dose reduction or cessation. The mech-
anism for myopic shifting is similar to
anticholinergic effects where the ciliary
body becomes edematous, resulting in
thickening and anterior movement of the
lens. A major hypersensitivity reaction to
systemic and topically administered
sulfonamide drugs is Stevens-Johnson
syndrome.8
Tetracyclines
Tetracycline is also an effective
bacteriostatic drug against gram-positive
and gram-negative organisms. Some-
times, the periorbital area becomes
hyperpigmented and dark deposits may
occur in the palpebral conjunctiva. Tetra-
cycline and its derivative, minocycline,
can also cause pseudotumor cerebri with
extraocular muscle paresis especially in
children.8 Symptoms usually develop be-
tween 12 hours and four days after begin-
ning therapy. After discontinuing the
drug, these symptoms regress. Other re-
ported side effects include transient myo-
pia, decreased vision, photophobia and
diplopia.
Antimalarials
In addition to malaria, these drugs are
used to treat rheumatoid arthritis and
lupus. The optimal dosage is 3.5-4.0
mg/kg/day for chloroquine (Aralen) and
6.0- 6.5 m g/ kg/ day f or h y d r o x y -
chloroquine (Plaquenil).7 Chloroquine
tends to be more toxic than hydroxy-
chloroquine. The risk of irreversible reti-
nal damage is dose-dependent. The likeli-
hood increases when the total cumulative
dose exceeds 300g. 8 Toxic macular
changes have been well documented.
This bulls-eye maculopathy starts as fine
pigmentary mottling within the macular
area, with or without the loss of the foveal
reflex. The end result can range from re-
duced vision to possible blindness. Differ-
entials include retinitis pigmentosa and
age-related macular degeneration. The
pigmented tissues of the eye continue to
hold the drug for a prolonged period after
the drug has been discontinued according
to the melanin binding theory. This leads
to degenerative changes in the RPE.
Neurosensory retina has also been shown
to bind the drug.
Transient and reversible corneal
changes occur typically when the patient
receives more than 250 mg daily. 8
Whorl-like pigment deposits within the
corneal epithelium can occur from revers-
ible binding of the drug to intracellular
nucleoproteins in the corneal epithelium.7
In addition to the macular changes, op-
tic nerve pallor, cycloplegia and ptosis can
occur. A baseline exam should be per-
formed before the patient starts treatment.
Amsler grid to detect paracentral
Volume 11/2000/Number 6/Page 153
scotomas, color vision, contrast sensitiv-
ity and central red-white visual field can
be used to follow the patient for changes.7
Fundus photos are excellent for documen-
tation and useful for detecting subtle
changes in pigmentation.
Antitubercular
Isoniazid (INH) is used to treat
mycobacterial diseases like tuberculosis.6
It is less toxic than other drugs such as
ethambutol, and INH is now considered
the drug of choice. Patients with renal in-
sufficiency, or impaired ability to excrete
the drug, may be at greater risk for devel-
oping ocular toxicity. An uncommon but
serious complication of antitubercular
drug therapy is acquired optic neuropa-
thy.6 Both INH and ethambutol can cause
retrobulbar optic neuritis, but most cases
were reversible with INH only.17
ERECTILE DYSFUNCTION
Sildenafil (Viagra) is a new oral medi-
cation to treat males with erectile dysfunc-
tion. It inhibits phosophodiesterase-5
(PDE-5) which results in vasodilation of
smooth muscle.18 Visual disturbances are
a common side effect of this medication.
Viagra blocks hyperpolarization of
photoreceptors.7 Eleven percent of pa-
tients on 100mg perceived a blue haze up
to four hours after administration. This
may cause difficulty in distinguishing be-
tween blue and green. Since pilots and
aviators need to see blue runway lights,
they should be cautioned for safety. The
Federal Aviation Administration has rec-
ommended that pilots not fly within six
hours of taking the drug.18 Caution should
also be used in patients with retinitis
pigmentosa due to the uncertainty about
long-term retinal damage.
SUMMARY
A careful and detailed case history is
important to reveal a patients medication
history. The ocular and visual side effects
from a patients systemic medication can
range from mild to severe. These side ef-
fects may or may not be serious enough to
warrant discontinuing treatment. Recog-
nition of ocular and visual side effects is
important for prompt management to pre-
vent and minimize serious complications.
Familiarity with medications improves by
routinely paying attention to concomitant
medications. While these considerations
should be in the minds of all optometrists,
Volume 11/2000/Number 6/Page 154
they are particularly important for those
who are increasingly called upon to diag-
nose and treat the functional visual prob-
lems of at risk populations.
REFERENCES
1. Jaanus SD, Bartlett JD, Hiett, JA. Ocular effects
of systemic drugs. In: Bartlett JDand Jaanus SD,
eds. Clinical Ocular Pharmacology, 3rd ed.
Boston: Butterworth-Heinemann, 1995:957-
1006.
2. Koneru PB, Lien EJ, Koda RT. Review:
Oculotoxicities of systemically administered
drugs. J Ocular Pharm 1886;2(4):385-399.
3. M y c e k M J , H a r ve y R A , C ha m pe P C .
Lippincotts Illustrated Reviews: Pharmacol-
ogy, 2nd ed. Philadelphia: Lippincott-Raven,
1997.
4. Muchnick BG. The ocular manifestations of sys-
temic drugs. Optom Today 1998 May:44-52.
5. Bartlett JD. Ophthalmic toxicity by systemic
drugs. In: GCY Chiou, ed. Ophthalmic Toxicol-
ogy, 2nd ed. Michigan: Taylor and Francis,
1999:225-283.
6. To HT, Townsend JC. Ocular toxicity of sys-
temic medications: a case series. J Am
OptomAssoc 2000;71(1):29-29.
7. Moorthy RS, Valluri S. Ocular toxicity associ-
ated with systemic drug therapy. Curr Opin
Ophthalmol 1999;10(6):438-446.
8. Woodard DR, Woodard RB. Drugs in Primary
Eyecare, 2nd ed. Connecticut: Appleton and
Lange, 1997.
9. Fraunfelder FT, Herrin S. A practical guide to
drug induced ocular side effects. Rev
Ophthalmo 1997;4(7):78-80, 85-87.
10. Levine L. Optometrically-relevant side effects
of the systemic drugs most frequently prescribed
in 1991. J Behav Optome 1992;3(5):115-119.
11. Hom M. Is it the medication? Optom Mg, 2000;
35(2):92-96.
12. Patel M. Ocular side-effects of systemic drugs:
Part 2. Optom Today UK 1999;39(7):43-47.
13. Trachtman JN. The efficacy of ritalin for hyper-
active children. JBehav Optom 1992;2(7):
179-185.
14. Novack GD. Ocular toxicology. Curr Opin
Ophthalmol 1997;8(6):88-92.
15. Ajamian PC. When systemic drugs cause trou-
ble in the eye. Rev Optom 1995;132(11):
136-137.
16. Jaanus SD. Ocular side effects of selected sys-
temic drugs. Optom Clin 1992;2(4):73-96.
17. Bright DC. What you may not know about
over-the-counter drugs. Optom Mgt 1992;27(1):
57-61.
18. Marmor MF, Kessler R. Sildenafil (Viagra) and
ophthalmology. Surv Ophthalmol 1999;
44(2):153-162.
Corresponding author:
Valerie Q. Wren, O.D.
State University of New York
State College of Optometry
33 West 42nd Street
New York, NY 10036-3610
Date accepted for publication:
July 7, 2000
n Journal of Behavioral Optometry
 Appendix A. Common Systemic Medications and Uses
ANTI-HYPERTENSIVES THYROID HORMONE ANTI-COAGULANTS
Ace inhibitor SYNTHROID levothyroxine Coumadin derived
CAPOTEN captopril COUMADIN (po)
ESTROGEN HORMONE HEPARIN (iv)
VASOTEC enalapril ESTRADERM estradiol
ZESTRIL lisinopril PANWARFIN (po)
PREMARIN estrogen Platelet inhibitor
Alpha agonist
ALDOMET methyldopa ANTI-PSYCHOTICS PLAVIX clopidogrel
CATAPRES clonidine Phenothiazines TICLID ticlopidine
MINIPRESS prazosin MELLARIL thioridazine ANALGESICS
Bblockers THORAZINE chlorpromazine ASPIRIN salicyclate
COGARD nadolol STELLAZINE trifluoroperazine
INDERAL propanolol Manic Depressives CORTICOSTEROIDS
LOPRESSOR metoprolol HALDOL haloperidol Systemic
TENORMIN atenolol CIBALITH-S lithium DECADRON dexamethasone
ESKALITH DELTASONE prednisone
CHF LITHIONATE Inhalers
Thiazides/Diuretics NASALIDE flunisolide
HCTZ hydrochlorthiazide ANTI-ANXIETY VANCENASE beclomethasone
LASIX furosemide ATIVAN lorazepam
HALCION triazolam NSAIDS
ANTI-ANGINAL LIBRIUM chlordiazepoxide ADVIL ibuprofen
Antiarrhythmia KLONOPIN clonazepam INDOCIN indomethacin
CORDARONE amiodarone VALIUM diazepam ORUDIS ketoprofen
Ca++Channel Blocker VERSED midozolam ALEVE naproxen
CALAN verapamil XANAX alprazolam
NORVASC amlopidine ARTHRITIS
PROCARDIA nifedipine ANTI-DEPRESSANTS RIDAURA auranofin
Vasodilators Heterocyclics CELEBREX celecoxib
ISOSORDIL isosorbide EFFEXOR venlafaxine VIOXX refecoxib
LONITEN minoxidil DESYREL trazodone
Nitroglycerin Tricyclics ALLERGY
ELAVIL amitriptyline BENADRYL diphenhydramine
NITROBID nitroglycerin
ADAPIN doxepin CHLORTRIMETON
CHF / ARRHYTHMIA SINEQUAN chlorpheniramine
Cardiac Glycosides PAMELOR nortriptyline
DIGOXIN digitalis
ANTI-CHOLINERGIC
AVENTYL TRANSDERM SCOP
CHOLESTEROL Serotonin inhibitor scopolomine
MEVACOR lovastatin PROZAC fluoxetine
ZOCOR simvastatin ZOLOFT sertraline DERMATOLOGICS
ACCUTANE isoretinoin
NIACOR niacin (B3) BARBITURATES
DIABETES AMYTAL amobarbital ANTI-TUBERCULAR
BUTISOL butabarbital LANIAZID isoniazid
Sulfonylureas
SECONAL secobarbital MYAMBUTOL ethambutol
DYMELOR acetohexamide
RIFATER rifampin
DIABINESE chlorpropamide ANTI-CONVULSANTS
GLUCOTROL glipizide DILANTIN phenytoin ERECTILE DYSFUNCTION
MICRONASE glyburide TEGRETOL carbamazepine VIAGRA sildenafil
GLUCOPHAGE metformin
TOLINASE tolazamide CNS STIMULANT
ORINASE tolbutamide RITALIN
Insulin methylphenidate
HUMULIN
NOVOLIN
ANTI-MIGRAINE
Serotonin agonist
ORAL CONTRACEPTIVES IMITREX sumatriptan
DEMULEN
LOESTRIN
ANTI-ULCER
PEPCID famotidine
LO-OVRAL
AXID nizatidine
MODICON
PRILOSEC omeprazole
NORDETTE
CARAFATE sucrafate
NORINYL
ORTHO-NOVUM
ORTHO-TRICYCLEN
OVCON
OVRAL

n Journal of Behavioral Optometry Volume 11/2000/Number 6/Page 155

 Appendix B. Summary of the Ocular
CARDIOVASCULAR TEARS LIDS/CONJ EOMS CORNEA PUPIL ACCOM
BBlockers Dry Eye Diplopia
Diuretics Dry Eye Myopia
Amiodarone Dry Eye Nystagmus Whorl-like deposits
Nitroglycerin
Digoxin Diplopia Edema Mydriasis
HYPERLIPIDEMICS
Niacin Dry Eye Edema Diplopia
HYPERGLYCEMICS Paresis,Diplopia
HORMONES
Thyroid replacement Hyperemia
Oral Contraceptives Dry Eye Diplopia Mydriasis

Estrogen replacement CL intol

CNS
Phenothiazines
Dry Eye Blue conj Diplopia Endothelial pigment Mydriasis Cycloplegia
(chlorpromazine)
Manic-depressives Jerk nystagmus
CL intol Decr accom
(lithium) Diplopia
Antianxiety Dry Eye Allergic CJ Diplopia Mydriasis Decr accom
Antidepressants
Dry Eye Diplopia Cycloplegia
(TCAs)
Barbiturates Ptosis Nystagmus Mydriasis
Anticonvulsants Chronic CJ Nystagmus Mydriasis
CNS stimulant (Ritalin) Mydriasis Decr accom
ANTIULCER Hyperemia,CJ Decr accom
ANTICOAGULANTS
ANALGESICS Allergic CJ Nystagmus Exacerbates HSK Mydriasis
CORTICOSTEROIDS Blue conj Diplopia Stromal opacities Mydriasis
NSAIDS Dry Eye Diplopia
ANTIRHEUMATIC
Gold salts Gold deposits Nystagmus Chrysiasis
Cox 2 inhibitors
ANTIHISTAMINES Dry Eye Nystagmus Mydriasis Decr accom
DERMATOLOGIC Keratitis, Deposits,
Dry Eye Blepharo CJ Myopia
(isoretinoin) Neovascularization
ANTI-INFECTIVES
Sulfonamides CJ, Edema Myopia
Tetracyclines Dark deposits Paresis,Diplopia
Antimalarials Ptosis Nystagmus Whorl-like deposits Cycloplegia
Antitubercular
Diplopia Mydriasis
(ethambutol)
Antiviral (acyclovir)
OTHER
Viagra

Volume 11/2000/Number 3/Page 156 n Journal of Behavioral Optometry

and Visual Side Effects of Drugs
LENS IOP RETINA COLOR ON Other
Decr IOP Visual hallucinations
Color change
ASC Color change Optic neuropathy Halos, Blurred vision, Photophobia
Yellow/Blue halos
Decr IOP Yellowing Flickering vision

CME Blurred vision

Optic neuritis

PTC Visual hallucinations

Macular edema, PTC
Vascular occlusions

ASC Incr IOP RPE changes Blurred vision

Blurred vision

Retinal hemes Blurred vision

Incr IOP

Color change Glare

Cat Color change Blurred vision
Visual hallucinations, Blurred vision
Color change Spontaneous AC hyphema
Retinal hemes
Retinal hemes Yellowing Iris microcysts
PSC Incr IOP Retinopathy Color change PTC VA/VF loss, Blurred vision
RPE changes Color change Optic neuritis

ASC Ret hemes Blurred vision

Blurred vision
Incr IOP Ret hemes
Cat Night blindness / PTC / Optic neuritis
retinotoxicity

Ret hemes Optic neuritis

Ret hemes PTC
Toxic maculopathy Color change Optic atrophy
Color change Retrobulbar Optic
neuritis
Visual hallucinations

Blue haze

n Journal of Behavioral Optometry Volume 11/2000/Number 3/Page 157